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Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice

Abstract

Aged humans sustain a high rate of epithelial cancers such as carcinomas of the breast and colon, whereas mice carrying common tumour suppressor gene mutations typically develop soft tissue sarcomas and lymphomas. Among the many factors that may contribute to this species variance are differences in telomere length and regulation. Telomeres comprise the nucleoprotein complexes that cap the ends of eukaryotic chromosomes and are maintained by the reverse transcriptase, telomerase1. In human cells, insufficient levels of telomerase lead to telomere attrition with cell division in culture2 and possibly with ageing and tumorigenesis in vivo3,4,5. In contrast, critical reduction in telomere length is not observed in the mouse owing to promiscuous telomerase expression and long telomeres6,7,8,9,10. Here we provide evidence that telomere attrition in ageing telomerase-deficient p53 mutant mice promotes the development of epithelial cancers by a process of fusion-bridge breakage that leads to the formation of complex non-reciprocal translocations—a classical cytogenetic feature of human carcinomas. Our data suggest a model in which telomere dysfunction brought about by continual epithelial renewal during life generates the massive ploidy changes associated with the development of epithelial cancers.

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Figure 1: Kaplan–Meier analysis of tumour incidence in p53 mutant mice divided on the basis of generation of telomerase deficiency.
Figure 2: Histology of epithelial cancers in mice with telomere dysfunction.
Figure 3: Spectral karyotyping.

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Acknowledgements

We thank D. Castrillon for advice on tumour analysis; S. Ye for technical assistance; M. Novotny and C. Lam for technical assistance with histopathology; L. Rudolph, K. Wong, N. Sharpless, C. Khoo and N. Schreiber-Agus for critical reading of the manuscript. This work was supported by grants from the NIH to R.A.D. S.E.A. is a Howard Hughes Physician Postdoctoral Fellow and supported by a grant from the Massachusetts Department of Public Health. L.C. is a V foundation scholar and is supported by a NIH Mentored Clinician Scientist Award. R.A.D. is an American Cancer Society Professor. SKY analysis was performed in the Arthur and Rochelle Belfer Cancer Genomic Center at the Dana-Farber Cancer Institute.

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Correspondence to Ronald A. DePinho.

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Artandi, S., Chang, S., Lee, SL. et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406, 641–645 (2000). https://doi.org/10.1038/35020592

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